Membrane-based immunotherapy for triple negative breast cancer- a partnered approach

基于膜的三阴性乳腺癌免疫疗法——一种合作方法

基本信息

批准号：
9895637
负责人：
CHRISTOPHER D PACK
金额：
$ 48.09万
依托单位：
EMORY UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-04-01 至 2021-09-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9895637
关键词：
4T1 Address Adjuvant Affect Agreement Aliquot Allogenic Antigen Targeting Antigens Applications Grants Area Autologous Award Biological Biological Response Modifier Therapy Biological Sciences Breast Cancer Model Breast Cancer Patient CD34 gene CD80 gene Cancer Patient Cancer Vaccines Cells Clinic Clinical Protocols Clinical Trials Data Development Disease ERBB2 gene Estrogen Receptors Excision Freezing Future Gene Mutation Gene Transfer Genes Globo-H Glycolipids Grant Heterogeneity Human Immobilization Immune Immune response Immune system Immunity Immunization Immunodeficient Mouse Immunotherapy Implant Injections Interleukin-12 Knowledge Liver Malignant Neoplasms Medical Membrane Methods Modeling Mucins Mus Nature Neoadjuvant Therapy Neoplasm Metastasis Operative Surgical Procedures Patients Peptides Pharmaceutical Preparations Phase Preparation Prior Chemotherapy Process Progesterone Receptors Property Proteins Recommendation Research Personnel Small Business Innovation Research Grant Surface Antigens System Technology Technology Transfer Testing Therapeutic Thymus Gland Translating Tumor Antigens Tumor Cell Line Tumor Tissue Tumor-Derived Tumor-infiltrating immune cells United States National Institutes of Health Universities Vaccination Vaccine Adjuvant Vaccine Therapy Vaccines Vesicle Xenograft Model Xenograft procedure anti-cancer anti-tumor immune response base cancer immunotherapeutics cancer immunotherapy cancer subtypes chemotherapy cost cost effective cytokine design effective therapy efficacy testing established cell line humanized mouse immune activation immune checkpoint blockade inhibitor/antagonist malignant breast neoplasm melanoma mouse model novel novel therapeutics outcome forecast overexpression patient variability personalized immunotherapy pre-clinical preclinical study prevent public health relevance reconstitution small molecule therapeutics standard of care therapeutic evaluation therapeutic target therapeutic vaccine triple-negative invasive breast carcinoma tumor tumor heterogeneity tumor xenograft uptake

项目摘要

DESCRIPTION (provided by applicant): Recent approval of anti-cancer immunotherapeutic drugs by the FDA validates that stimulation of the immune system of a cancer patient is an effective way to control or prevent metastatic disease. However, the approved immune checkpoint blockade inhibitors are effective only in a subset of melanoma patients, and a majority of the cancer patients do not respond to the drugs. Moreover, cancers such as breast cancers do not respond well to these drugs, suggesting additional immune stimulatory approaches such as therapeutic vaccination need to be developed. One of the major problems in developing vaccination-based immunotherapies for cancer is the heterogeneous nature of the disease. Recent deep gene sequencing studies demonstrated extensive intratumoral and interpersonal heterogeneity in gene mutations in tumors. Therefore, developing a therapeutic vaccine using a single antigen/peptide or patient-derived autologous/allogeneic tumor cell lines, which may not represent the heterogeneity of tumors, would not result in an immune response against the breadth of tumor antigens. Therefore, to induce immunity against the specific antigenic signature of a patient, use of an optimally adjuvanted vaccine based on whole autologous tumor tissue is highly desirable. We have developed an adjuvanted whole tumor tissue based vaccine for cancer immunotherapy using tumor membrane vesicles (TMVs) prepared from whole tumor tissue and modifying them by incorporating immunostimulatory molecules (ISMs) such as B7-1 and IL-12 using a novel protein transfer method. This method immobilizes ISMs onto TMVs via a glycolipid anchor (GPI), resulting in simultaneous delivery of TMVs along with biological adjuvants to APCs for enhanced uptake and optimal immune cell activation. Based on promising preclinical data in mice, Emory University and Metaclipse Therapeutics Corporation have entered into an agreement to advance this immunotherapy approach to clinics targeting triple negative breast cancer (TNBC). This subtype of cancer is highly heterogeneous and target antigens vary from patient to patient, thus making it an ideal target for our personalized immunotherapy. Metaclipse was awarded an NIH Phase I SBIR grant to further validate the technology in a TNBC model and is currently conducting studies required for IND filing. In this partnership grant application we propose to: 1) Perform preclinica studies to make recommendations on the use of the TMV-based, patient-specific immunotherapy in combination with standard-of-care treatments, 2) Investigate the effect of neoadjuvant chemotherapy on the yield and biological activity of the TMV-based immunotherapy prepared from mouse tumor tissue and human tumor tissue derived from patient-derived xenograft (PDX) models as well as TNBC patients and 3) Evaluate the TMV-based immunotherapy approach using human TNBC tumor tissue and human GPI-ISMs in a PDX model engrafted with a human immune system. The knowledge obtained from the proposed collaborative studies between Emory University and Metaclipse will aid in designing a clinical trial strategy for TMV-based immunotherapy in TNBC patients.

描述（由申请人提供）： FDA 最近批准的抗癌免疫治疗药物证实了刺激癌症患者的免疫系统是控制或预防转移性疾病的有效方法。然而，批准的免疫检查点阻断抑制剂是有效的。仅在一部分黑色素瘤患者中，大多数癌症患者对这些药物没有反应，此外，乳腺癌等癌症对这些药物反应不佳，这表明需要采取其他免疫刺激方法，例如治疗性疫苗接种。开发基于疫苗的癌症免疫疗法的主要问题之一是该疾病的异质性，最近的深度基因测序研究表明肿瘤基因突变存在广泛的瘤内和人际异质性。单一抗原/肽或患者来源的自体/同种异体肿瘤细胞系可能不代表肿瘤的异质性，不会导致针对多种肿瘤抗原的免疫反应，因此，诱导针对特定抗原特征的免疫。对于患者来说，使用基于完整自体肿瘤组织的最佳佐剂疫苗是非常理想的，我们开发了一种基于佐剂的完整肿瘤组织的疫苗，用于使用从整个肿瘤组织制备的肿瘤膜囊泡（TMV）并通过掺入对其进行修饰。该方法使用新型蛋白质转移方法将 B7-1 和 IL-12 等免疫刺激分子 (ISM) 通过糖脂锚 (GPI) 固定到 TMV 上。基于小鼠中令人鼓舞的临床前数据，埃默里大学和 Metaclipse Therapeutics Corporation 已达成协议，将这种免疫治疗方法推广到针对三阴性的临床。乳腺癌（TNBC）这种癌症亚型具有高度异质性，不同患者的靶抗原也不同，因此使其成为我们个性化免疫治疗的理想靶点。 I 期 SBIR 拨款用于进一步验证 TNBC 模型中的技术，目前正在开展 IND 备案所需的研究。在本次合作拨款申请中，我们建议：1) 进行临床前研究，就基于 TMV 的患者使用提出建议。 -特异性免疫疗法与标准护理治疗相结合，2) 研究新辅助化疗对由小鼠肿瘤组织和源自患者的人类肿瘤组织制备的基于 TMV 的免疫疗法的产量和生物活性的影响异种移植 (PDX) 模型以及 TNBC 患者，3) 在植入人类免疫系统的 PDX 模型中使用人类 TNBC 肿瘤组织和人类 GPI-ISM 评估基于 TMV 的免疫治疗方法。埃默里大学和 Metaclipse 将协助设计 TNBC 患者基于 TMV 的免疫疗法的临床试验策略。